Derivatives of probucol have been developed as therapeutics, for example, for the treatment of cardiovascular disease and as anti-inflammatory agents. Probucol contains two hydroxyl groups and can be modified to form mono-substituted or di-substituted derivatives. In particular, mono-substituted derivatives, for example, mono-ethers and mono-esters of probucol have been found to have useful therapeutic properties. Mono-esters and ethers of probucol have been reported to be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and dermatitis. See, for example, U.S. Pat. No. 6,147,250. Methods for treating transplant rejection using mono-substituted derivatives of probucol also have been reported. See U.S. Patent Publication No. 2004/138147. Of particular interest are monoester derivatives of probucol that include a carboxyl group, such as the following compound, which has been shown, when dosed orally, to block VCAM-1 expression, reduce atherosclerosis and have potent anti-oxidant activity:

U.S. Pat. No. 5,262,439 discloses that carboxylic acid derivatives of probucol compounds can be prepared by treating probucol compounds with an excess of dicarboxylic acid anhydride and catalytic amounts of 4-dimethylamino pyridine at a temperature sufficient to ensure that the dicarboxylic acid anhydride is liquid.
U.S. Pat. No. 6,147,250 discloses that monoesters of probucol can be prepared by treating probucol in tetrahydrofuran with sodium hydride and an acid chloride or acid anhydride. In one example using this process, a monoester of probucol is prepared in approximately 14% yield following purification by chromatographic methods.
U.S. Pat. No. 6,323,359 discloses methods of manufacturing probucol derivatives. The '359 patent discloses the use of alkali metal hydroxide, alkali metal alkoxide, alkali ammonium alkoxide, and alkyl ammonium hydroxide to form salts of the probucol derivative compounds and then reacting the salts with a dicarboxylic acid anhydride.
U.S. Patent Publication No. 2004/0204485 discloses processes for the preparation of esters and ethers of probucol by reacting probucol or a free hydroxyl-containing probucol derivative with a Grignard reagent or a lithium reagent to form a magnesium or lithium salt, followed by a reaction with an ester-forming or ether-forming compound. The method described for separating the mono-esters from the di-esters is similar to the '359 patent.
U.S. Patent Publication No. 2005/0267187 discloses additional processes for the preparation of esters and ethers of probucol and also uses a method described for separating the mono-esters from the di-esters similar to the '359 patent.
A series of French patents have disclosed that certain probucol derivatives are hypocholesterolemic and hypolipemic agents: Fr 2.168.137 (bis-4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2.140.769 (benzofuryloxyalkanoic acid derivatives of probucol); Fr 2.134.810 (bis-(3-alkyl-5-alkyl-4-thiazole-5-carboxy)phenylthio)alkanes); Fr 2.133.024 (bis-(4-nicotinoyloxyphenylthio)-propanes); and Fr 2.130.975 ((bis-(4-phenoxyalkanoyloxy)-phenylthio)alkanes). French Patent Publication No. 2,168,137 describes the production of diesters of probucol by reacting probucol with a halide or anhydride of an organic acid in an inert solvent with heat and in the presence of a base such as an alkaline hydroxide or carbonate, or a tertiary amine (for example, triethylamine). The O-metal salt derivative of probucol is also suggested to be useful as the reaction intermediate.
A number of methods for the synthesis and isolation of mono-substituted probucol derivatives have been described in the art. In general, the synthesis of the mono-substituted derivative also produces the di-substituted derivative. Of particular challenge is the separation of the mono-substituted derivative from the di-substituted derivative from the mixture resulting from the synthesis steps.
It is an object of the invention to provide efficient methods of separating mono-carboxy substituted probucol derivatives from di-carboxy substituted probucol derivatives.